Relationships between steady-state and single-dose plasma drug concentrations for pharmacokinetic systems with nonlinear elimination

Equations were examined to predict or correlate steady-state (SS) plasma concentrations and single-dose (SD) data for pharmacokinetic systems with various types of input and nonlinear elimination. The effects of variation of the Michaelis-Menten parameters, input rate of drug, or bioavailability on the predictability of steady-state plasma concentrations from single-dose data were demonstrated by computer simulations for a one-compartment model. Use of apparently linear equations with Michaelis-Menten parameters to predict steady-state plasma concentrations from single dose data is adequate only in limiting low single-dose cases. Linear SS versus SD correlations for both intravenous and oral dosing can be observed in population data only when Km is the principal variable; other conditions produce curvilinear behavior. Equations to calculate values of the Michaelis-Menten parameters from dual single-dose and steady-state AUC values are derived and tested for drugs which are intravenously administered. These equations and simulations provide insight into factors determining the relationship between SS and SD AUC for drugs with nonlinear elimination.